Association of subclinical hypothyroidism and cardiovascular disease with mortality
Open accessAbstract
Importance: Subclinical hypothyroidism is a common clinical entity among US adults associated in some studies with an increase in the risk of cardiovascular disease (CVD) and mortality. However, the extent to which CVD mediates the association between elevated serum thyrotropin (TSH) and mortality has not yet been well established or sufficiently quantified. Objective: To elucidate the extent to which subclinical hypothyroidism, elevated serum TSH and normal serum free thyroxine, or high-normal TSH concentrations (ie, upper normative-range TSH concentrations) are associated with mortality through CVD among US adults. Design, Setting, and Participants: This cohort study relied on representative samples of US adults enrolled in the National Health and Nutrition Examination Survey in 2001 to 2002, 2007 to 2008, 2009 to 2010, and 2011 to 2012 and their mortality data through 2015. Data were analyzed from January to August 2019. Main Outcomes and Measures: Cox proportional hazards regression models were used to investigate associations between the TSH concentration category (subclinical hypothyroidism or tertiles of serum TSH concentrations within the reference range; low-normal TSH, 0.34-1.19 mIU/L; middle-normal TSH, 1.20-1.95 mIU/L; and high-normal TSH, 1.96-5.60 mIU/L) and all-cause mortality. Mediation analysis was used within the counterfactual framework to estimate natural direct associations (not through CVD) and indirect associations (through CVD). Results: Of 9020 participants, 4658 (51.6%) were men; the mean (SD) age was 49.4 (17.8) years. Throughout follow-up (median [interquartile range], 7.3 [5.4-8.3] years), serum thyroid function test results consistent with subclinical hypothyroidism and high-normal TSH concentrations were both associated with increased all-cause mortality (subclinical hypothyroidism: hazard ratio, 1.90; 95% CI, 1.14-3.19; high-normal TSH: hazard ratio, 1.36; 95% CI, 1.07-1.73) compared with the middle-normal TSH group. Cardiovascular disease mediated 14.3% and 5.9% of the associations of subclinical hypothyroidism and high-normal TSH with all-cause mortality, respectively, with the CVD mediation being most pronounced in women (7.5%-13.7% of the association) and participants aged 60 years and older (6.0%-14.8% of the association). Conclusions and Relevance: In this study, CVD mediated the associations of subclinical hypothyroidism and high-normal TSH concentrations with all-cause mortality in the US general population. Further studies are needed to examine the clinical benefit of thyroid hormone replacement therapy targeted to a middle-normal TSH concentration or active CVD screening for people with elevated TSH concentrations.
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TL;DR
In a nationally representative NHANES cohort of 9020 US adults, higher thyrotropin (TSH) concentrations—including subclinical hypothyroidism and high-normal TSH—were associated with increased all-cause mortality. Cardiovascular disease mediated 14.3% of the subclinical hypothyroidism association and 5.9% of the high-normal TSH association with all-cause mortality.
Key findings
- During a median follow-up of 7.3 years, 435 deaths occurred. Compared with middle-normal TSH, adjusted hazard ratios for all-cause mortality were 1.36 (95% CI, 1.01-1.83) for low-normal TSH, 1.36 (95% CI, 1.07-1.73) for high-normal TSH, and 1.90 (95% CI, 1.14-3.19) for subclinical hypothyroidism; restricted cubic splines showed a U-shaped association between TSH and mortality.
- CVD mediated 14.3% of the association of subclinical hypothyroidism with all-cause mortality and 5.9% of the association of high-normal TSH with all-cause mortality; no evidence of CVD mediation was found for low-normal TSH.
- In sex-stratified analyses, CVD mediated 7.5% to 13.7% of the associations of high-normal TSH or subclinical hypothyroidism with mortality in women, with no or only slight mediation in men. In participants aged 60 years or older, CVD mediated 6.0% of the high-normal TSH association and 14.8% of the subclinical hypothyroidism association, but the indirect effect confidence interval for subclinical hypothyroidism included the null.
Methods
- Secondary analysis of the US National Health and Nutrition Examination Survey (NHANES), including four cycles (2001-2002, 2007-2008, 2009-2010, 2011-2012), among adults aged 20 years or older with serum TSH and free thyroxine data; after exclusions, the final analytical cohort was 9020 participants, followed for mortality through December 2015.
- TSH categories were low-normal (0.34-1.19 mIU/L), middle-normal (1.20-1.95 mIU/L), high-normal (1.96-5.60 mIU/L), and subclinical hypothyroidism (TSH >5.60 mIU/L with normal free thyroxine); CVD was ascertained by self-report at baseline.
- Multivariable Cox proportional hazards models and restricted cubic splines estimated mortality associations; mediation analysis used a marginal structural counterfactual approach, with 1000 bootstrap samples for bias-corrected 95% confidence intervals.
Limitations
- The paper states that it could not account for trends or changes in thyroid function over follow-up; exposure-mediator timing was not well defined, so reverse causation is possible; CVD and other medical histories were self-reported and may be misclassified; mediation analysis assumed no unmeasured confounders and no mediator-outcome confounding affected by exposure; and not all CVD events during follow-up were captured, so CVD mediation may be underestimated.
- Evident from the design: this is an observational cohort, so causal inferences are limited, and thyroid exposure was based on baseline TSH/free thyroxine measurements rather than longitudinal thyroid function.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Claims the paper makes
0 of 57 cited sources checked · 0 supported · 0 flagged
- Findingown data
Cardiovascular disease mediated 14.3% of the association between subclinical hypothyroidism and all-cause mortality in US adults.
“We estimated that CVD mediated 14.3% and 5.9% of the association of subclinical hypothyroidism and high-normal TSH with all-cause mortality, respectively (Table 3).”
Quote in the paperSubstantial claim- Rests on an assumption: Self-reported coronary artery disease and nonfatal cardiovascular disease events accurately classify prevalent cardiovascular disease.
- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: The mediation analysis assumes no unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships.
- Findingown data
There was no evidence for mediation through cardiovascular disease for low-normal TSH levels and all-cause mortality.
“We did not find any evidence for mediation through CVD for low-normal TSH levels and all-cause mortality.”
Quote in the paperSubstantial claim- Rests on an assumption: Self-reported coronary artery disease and nonfatal cardiovascular disease events accurately classify prevalent cardiovascular disease.
- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: The mediation analysis assumes no unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships.
- Findingown data
Compared with middle-normal TSH, high-normal TSH is associated with higher all-cause mortality (HR 1.36, 95% CI 1.07-1.73) in US adults.
“high-normal TSH group (hazard ratio, 1.36; 95% CI, 1.07-1.73)”
Quote in the paperSubstantial claim- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: A single baseline serum TSH measurement adequately represents long-term thyroid function.
- Findingown data
There was no evidence for cardiovascular disease mediation between low-normal TSH and all-cause mortality overall or stratified by sex and age.
“We did not find evidence for CVD mediation between low-normal TSH and all-cause mortality overall or stratified by sex and age.”
Quote in the paperSubstantial claim- Rests on an assumption: Self-reported coronary artery disease and nonfatal cardiovascular disease events accurately classify prevalent cardiovascular disease.
- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: The mediation analysis assumes no unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships.
- Findingown data
In men, there was no mediation or only slight mediation through cardiovascular disease for the associations of high-normal TSH or subclinical hypothyroidism with all-cause mortality.
“while we found no mediation or only a slight mediation through CVD in men (Table 4).”
Quote in the paperSubstantial claim- Rests on an assumption: Self-reported coronary artery disease and nonfatal cardiovascular disease events accurately classify prevalent cardiovascular disease.
- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: The mediation analysis assumes no unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships.
- Findingown data
In participants aged 60 years or older, cardiovascular disease mediated 6.0% of the association of high-normal TSH with all-cause mortality.
“We also estimated that CVD mediated 6.0% of the associations of high-normal TSH with all-cause mortality for participants aged 60 years or older (eTable 4 in the Supplement).”
Quote in the paperNot a substantial claim- Rests on an assumption: Self-reported coronary artery disease and nonfatal cardiovascular disease events accurately classify prevalent cardiovascular disease.
- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: The mediation analysis assumes no unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships.
- Findingown data
Compared with middle-normal TSH, subclinical hypothyroidism is associated with higher all-cause mortality (HR 1.90, 95% CI 1.14-3.19) in US adults.
“subclinical hypothyroidism group (hazard ratio, 1.90; 95% CI, 1.14-3.19)”
Quote in the paperSubstantial claim- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: A single baseline serum TSH measurement adequately represents long-term thyroid function.
- Findingown data
In women, cardiovascular disease mediated 7.5% to 13.7% of the associations of high-normal TSH or subclinical hypothyroidism with all-cause mortality.
“In stratified analyses, we estimated that CVD mediated 7.5% to 13.7% of the associations of high-normal TSH or subclinical hypothyroidism with all-cause mortality in women”
Quote in the paperSubstantial claim- Rests on an assumption: Self-reported coronary artery disease and nonfatal cardiovascular disease events accurately classify prevalent cardiovascular disease.
- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: The mediation analysis assumes no unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships.
- Findingown data
In US adults from NHANES 2001-2012, after adjustment for model 2 confounders, serum TSH concentration has a U-shaped association with all-cause mortality risk.
“After adjusting for all potential confounders in model 2, restricted cubic splines showed a U-curved association between TSH and the risk of all-cause mortality (Figure).”
Quote in the paperSubstantial claim- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: A single baseline serum TSH measurement adequately represents long-term thyroid function.
- Findingown data
Compared with middle-normal TSH, low-normal TSH is associated with higher all-cause mortality (HR 1.36, 95% CI 1.01-1.83) in US adults.
“the hazard ratios for all-cause mortality were higher for the low-normal TSH group (hazard ratio, 1.36; 95% CI, 1.01-1.83)”
Quote in the paperSubstantial claim- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: A single baseline serum TSH measurement adequately represents long-term thyroid function.
- Findingown data
Cardiovascular disease mediated 5.9% of the association between high-normal TSH and all-cause mortality in US adults.
“We estimated that CVD mediated 14.3% and 5.9% of the association of subclinical hypothyroidism and high-normal TSH with all-cause mortality, respectively (Table 3).”
Quote in the paperSubstantial claim- Rests on an assumption: Self-reported coronary artery disease and nonfatal cardiovascular disease events accurately classify prevalent cardiovascular disease.
- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: The mediation analysis assumes no unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships.
- Findingown data
The mediation of CVD was observed particularly among women and participants aged 60 years and older when stratified by sex and age.
“The mediation of CVD was observed particularly among women and participants aged 60 years and older when stratified by sex and age.”
Quote in the paperSubstantial claim - Findingown data
CVD mediated 5.9% of the association between high-normal TSH and all-cause mortality among a representative sample of the US general adult population.
“Using mediation analysis, we found that CVD mediated 14.3% of the associations of subclinical hypothyroidism with all-cause mortality and 5.9% of the associations of high-normal TSH with all-cause mortality among a representative sample of the US general adult population.”
Quote in the paperSubstantial claim - Findingown data
CVD mediated 14.3% of the association between subclinical hypothyroidism and all-cause mortality among a representative sample of the US general adult population.
“Using mediation analysis, we found that CVD mediated 14.3% of the associations of subclinical hypothyroidism with all-cause mortality and 5.9% of the associations of high-normal TSH with all-cause mortality among a representative sample of the US general adult population.”
Quote in the paperSubstantial claim - Findingown data
There was no evidence of CVD mediation for the association between low-normal TSH and all-cause mortality.
“While low-normal TSH was associated with an increased risk of all-cause mortality, we did not find evidence of CVD mediation for this group.”
Quote in the paperSubstantial claim - Findingown data
CVD mediated the association between high-normal TSH and all-cause mortality.
“Moreover, CVD mediated the association between high-normal TSH and all-cause mortality.”
Quote in the paperSubstantial claim - Findingown data
The observed estimated indirect effect sizes were small for high-normal TSH.
“While the observed estimated indirect effect sizes were small for high-normal TSH, the impact of these associations should be considered, given that participants with high-normal TSH compose almost one-third of the total population (by definition) in the present study.”
Quote in the paperNot a substantial claim - Findingown data
Low-normal TSH was associated with an increased risk of all-cause mortality.
“While low-normal TSH was associated with an increased risk of all-cause mortality, we did not find evidence of CVD mediation for this group.”
Quote in the paperSubstantial claim - Findingown data
There is a U-curved association between serum TSH concentrations and risk of all-cause mortality, even within normative serum TSH and FT4 concentrations.
“In the present study, we found a U-curved association between serum TSH concentrations and risk of all-cause mortality, ie, even within normative serum TSH and FT4 concentrations.”
Quote in the paperSubstantial claim - Findingown data
In stratified analyses, mediation through CVD was most pronounced in women.
“In our stratified analyses, we found that mediation through CVD was most pronounced in women.”
Quote in the paperNot a substantial claim - Findingown data
The mediation of CVD on the association between higher TSH concentrations and all-cause mortality was observed only in older participants.
“The mediation of CVD on the association between higher TSH concentrations and all-cause mortality was observed only in older participants.”
Quote in the paperSubstantial claim - Study design and conductown data
Additional adjustment for diabetes, hypertension, statin prescription, and BMI did not alter the associations between TSH and all-cause mortality.
“Additional adjustment for indicators of metabolic disorders (ie, diabetes, hypertension, statin prescription, and BMI) did not alter these results (eFigure 2 and eTable 1 in the Supplement).”
Quote in the paperSubstantial claim- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: A single baseline serum TSH measurement adequately represents long-term thyroid function.
- Study design and conductown data
The proportional hazards assumption for TSH concentrations and cardiovascular disease was not violated.
“We confirmed that there was no evidence for violation of the proportional hazards assumption for TSH concentrations and CVD using Schoenfeld residuals (estat phtest in Stata).”
Quote in the paperSubstantial claim - Premisecitation
Inadequate serum thyroid hormone produces impairment of cardiac function.
“Inadequate serum thyroid hormone produces impairment of cardiac function and may result in bradycardia, endothelial dysfunction, increased intima-media thickness, diastolic dysfunction, increased vascular resistance, and pericardial effusion.3”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet. 2017; 390(10101): 1550- 1562. doi: 10.1016/S0140-6736(17)30703-1 28336049 PMC6619426 source
Not checked in the free run.
- Premisecitation
The TSH distribution differs by sex and age.
“As the TSH distribution differs by sex and age,30 stratum-specific analyses were conducted to estimate the associations of TSH with mortality according to sex (men and women) and age (<60 and ≥60 years) using category-specific tertiles to define low-normal, middle-normal, and high-normal TSH in each analysis.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Boucai L, Hollowell JG, Surks MI. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid. 2011; 21(1): 5- 11. doi: 10.1089/thy.2010.0092 21058882 PMC3012447 source
Not checked in the free run.
- Premisecitation
Recent individual patient meta-analysis by the Thyroid Studies Collaboration did not find higher risk of cardiovascular disease and all-cause mortality among adults with subclinical hypothyroidism compared with those with euthyroidism.
“Recent individual patient meta-analysis by the Thyroid Studies Collaboration8,9,10,11 did not find higher risk of CVD and all-cause mortality among adults with subclinical hypothyroidism compared with those with euthyroidism”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [8] Rodondi N, den Elzen WPJ, Bauer DC,; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010; 304(12): 1365- 1374. doi: 10.1001/jama.2010.1361 20858880 PMC3923470 source
Not checked in the free run.
- cites [9] Gencer B, Collet T-H, Virgini V,; Thyroid Studies Collaboration. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation. 2012; 126(9): 1040- 1049. doi: 10.1161/CIRCULATIONAHA.112.096024 22821943 PMC3884576 source
Not checked in the free run.
- cites [10] Collet T-H, Gussekloo J, Bauer DC,; Thyroid Studies Collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. 2012; 172(10): 799- 809. doi: 10.1001/archinternmed.2012.402 22529182 PMC3872478 source
Not checked in the free run.
- cites [11] Hyland KA, Arnold AM, Lee JS, Cappola AR. Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: the cardiovascular health study. J Clin Endocrinol Metab. 2013; 98(2): 533- 540. doi: 10.1210/jc.2012-2180 23162099 PMC3565111 source
Not checked in the free run.
- Premisecitation
Rhee and colleagues reported an association between high-normal TSH concentrations and mortality among people with chronic kidney disease, including those receiving dialysis.
“Rhee and colleagues15,16 have reported an association between high-normal TSH concentrations and mortality among people with chronic kidney disease, including those who are receiving dialysis.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [15] Rhee CM, Ravel VA, Streja E,. Thyroid functional disease and mortality in a national peritoneal dialysis cohort. J Clin Endocrinol Metab. 2016; 101(11): 4054- 4061. doi: 10.1210/jc.2016-1691 27525529 PMC5095247 source
Not checked in the free run.
- cites [16] Rhee CM, Kim S, Gillen DL,. Association of thyroid functional disease with mortality in a national cohort of incident hemodialysis patients. J Clin Endocrinol Metab. 2015; 100(4): 1386- 1395. doi: 10.1210/jc.2014-4311 25632971 PMC4399303 source
Not checked in the free run.
- Premisecitation
The thyroid hormone is one of the key regulators of cardiac function and cardiovascular hemodynamics.
“The thyroid hormone is one of the key regulators of cardiac function and cardiovascular hemodynamics; therefore, inadequate thyroid hormone levels impair the relaxation of vascular smooth muscle cells and decrease cardiac contractility by regulating calcium uptake and the expression of several contractile proteins in cardiomyocytes.37,38”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [37] Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007; 116(15): 1725- 1735. doi: 10.1161/CIRCULATIONAHA.106.678326 17923583 source
Not checked in the free run.
- cites [38] Owen PJD, Sabit R, Lazarus JH. Thyroid disease and vascular function. Thyroid. 2007; 17(6): 519- 524. doi: 10.1089/thy.2007.0051 17614771 source
Not checked in the free run.
- Study design and conductreasoning
We cannot rule out the risk of bias due to unmeasured confounders.
“Therefore, we cannot rule out the risk of bias due to unmeasured confounders.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: There are no other unmeasured confounders and no confounding between the mediator and outcome as affected by exposure.
- Study design and conductreasoning
As CVD and other medical histories were self-reported, the mediator and confounders might have been misclassified.
“Third, as CVD and other medical histories were self-reported, the mediator and confounders might have been misclassified.”
Quote in the paperNot a substantial claim - Study design and conductown data
The study had insufficient power to estimate statistically significant effect sizes in younger participants.
“We also found that high-normal TSH was associated with increased risk of all-cause mortality both in participants younger than 60 years and in those 60 years or older; however, we had insufficient power to estimate statistically significant effect sizes in younger participants, which will require larger studies with longer follow-up periods.”
Quote in the paperNot a substantial claim - Study design and conductcitation
The study used both serum TSH and FT4 to define subclinical hypothyroidism, which has not been implemented in previous studies using NHANES III owing to the lack of FT4 data.
“Moreover, we used both serum TSH and FT4 to define subclinical hypothyroidism, which has not been implemented in previous studies using NHANES III owing to the lack of FT4 data (ie, only total thyroxine data are available in NHANES III).5,29,44”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [5] Inoue K, Tsujimoto T, Saito J, Sugiyama T. Association between serum thyrotropin levels and mortality among euthyroid adults in the United States. Thyroid. 2016; 26(10): 1457- 1465. doi: 10.1089/thy.2016.0156 27539006 source
Not checked in the free run.
- cites [29] Rhee CM, Curhan GC, Alexander EK, Bhan I, Brunelli SM. Subclinical hypothyroidism and survival: the effects of heart failure and race. J Clin Endocrinol Metab. 2013; 98(6): 2326- 2336. doi: 10.1210/jc.2013-1039 23720788 PMC3667266 source
Not checked in the free run.
- cites [44] Hollowell JG, Staehling NW, Flanders WD,. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002; 87(2): 489- 499. doi: 10.1210/jcem.87.2.8182 11836274 source
Not checked in the free run.
- Interpretationreasoning
These biological mechanisms support the finding that CVD partially mediates the association of higher TSH concentrations with death.
“While the exact underlying mechanisms are still unclear, these biological mechanisms support our finding that CVD partially mediates the association of higher TSH concentrations with death.”
Quote in the paperSubstantial claim - Study design and conductnone given
It was not possible to consider any trends or changes in thyroid function over follow-up.
“First, it was not possible to consider any trends or changes in thyroid function over follow-up.”
Quote in the paperNot a substantial claim
- May combine two claims. 13
- Classified as probably not a substantial claim. 23
May combine two claims.
Findingown dataIn participants aged 60 years or older, cardiovascular disease mediated 14.8% of the association of subclinical hypothyroidism with all-cause mortality, but the 95% CI of the indirect effect included the null.
“A mediation through CVD was also estimated at 14.8% for subclinical hypothyroidism, but the 95% confidence interval of the estimated indirect effect size included the null, reflecting the smaller sample size.”
Quote in the paperNot a substantial claim- Rests on an assumption: Self-reported coronary artery disease and nonfatal cardiovascular disease events accurately classify prevalent cardiovascular disease.
- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: The mediation analysis assumes no unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships.
Classified as probably not a substantial claim.
FindingreasoningParticipants with high-normal TSH compose almost one-third of the total population (by definition) in the present study.
“While the observed estimated indirect effect sizes were small for high-normal TSH, the impact of these associations should be considered, given that participants with high-normal TSH compose almost one-third of the total population (by definition) in the present study.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLow-normal TSH concentrations were associated with all-cause mortality, especially in men and in the younger population.
“We also observed an association between low-normal TSH concentrations (ie, high-normal thyroid function) and all-cause mortality, especially in men and in the younger population.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHigh-normal TSH was associated with increased risk of all-cause mortality both in participants younger than 60 years and in those 60 years or older.
“We also found that high-normal TSH was associated with increased risk of all-cause mortality both in participants younger than 60 years and in those 60 years or older; however, we had insufficient power to estimate statistically significant effect sizes in younger participants, which will require larger studies with longer follow-up periods.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSubclinical hypothyroidism or high-normal TSH concentrations are associated with dyslipidemia, increased insulin resistance, and hypertension.
“Other epidemiological studies4,5,6,7 have also found an association between subclinical hypothyroidism or high-normal TSH concentrations (ie, serum TSH concentrations at the upper end of the normal range) and dyslipidemia, increased insulin resistance, and hypertension—components of metabolic syndrome.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [4] Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012; 379(9821): 1142- 1154. doi: 10.1016/S0140-6736(11)60276-6 22273398 source
Not checked in the free run.
- cites [5] Inoue K, Tsujimoto T, Saito J, Sugiyama T. Association between serum thyrotropin levels and mortality among euthyroid adults in the United States. Thyroid. 2016; 26(10): 1457- 1465. doi: 10.1089/thy.2016.0156 27539006 source
Not checked in the free run.
- cites [6] Garduño-Garcia J de J, Alvirde-Garcia U, López-Carrasco G,. TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects. Eur J Endocrinol. 2010; 163(2): 273- 278. doi: 10.1530/EJE-10-0312 20516204
Not checked in the free run.
- cites [7] Le TN, Celi FS, Wickham EP III. Thyrotropin levels are associated with cardiometabolic risk factors in euthyroid adolescents. Thyroid. 2016; 26(10): 1441- 1449. doi: 10.1089/thy.2016.0055 27599541 PMC5067795
Not checked in the free run.
May combine two claims.
Study design and conductown dataThe mediation results were not qualitatively altered by additional adjustment for metabolic disorder indicators or by using a different definition of the normal range for TSH.
“Additional adjustment for metabolic disorder indicators (ie, diabetes, hypertension, statin prescriptions, and BMI) or using a different definition of the normal range for TSH did not qualitatively alter these results (eTable 2 and eTable 3 in the Supplement).”
Quote in the paperNot a substantial claim- Rests on an assumption: Self-reported coronary artery disease and nonfatal cardiovascular disease events accurately classify prevalent cardiovascular disease.
- Rests on an assumption: Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
- Rests on an assumption: The mediation analysis assumes no unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships.
Classified as probably not a substantial claim.
PremisecitationSubclinical hypothyroidism is associated with cardiovascular abnormalities such as left ventricular dysfunction and impaired vascular relaxation.
“A previous review2 has reported cardiovascular abnormalities such as left ventricular dysfunction and impaired vascular relaxation among people with not only overt hypothyroidism but also subclinical hypothyroidism.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med. 2002; 137(11): 904- 914. doi: 10.7326/0003-4819-137-11-200212030-00011 12458990
Not checked in the free run.
Classified as probably not a substantial claim.
PremisereasoningThe potentially causal link between subclinical hypothyroidism, cardiovascular disease, and death remains unclear.
“Despite these mechanisms and evidence about the potential burden of elevated TSH on cardiac metabolism, the potentially causal link between subclinical hypothyroidism, cardiovascular disease (CVD), and death remains unclear.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationInadequate thyroid hormone levels impair the relaxation of vascular smooth muscle cells and decrease cardiac contractility by regulating calcium uptake and the expression of several contractile proteins in cardiomyocytes.
“The thyroid hormone is one of the key regulators of cardiac function and cardiovascular hemodynamics; therefore, inadequate thyroid hormone levels impair the relaxation of vascular smooth muscle cells and decrease cardiac contractility by regulating calcium uptake and the expression of several contractile proteins in cardiomyocytes.37,38”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [37] Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007; 116(15): 1725- 1735. doi: 10.1161/CIRCULATIONAHA.106.678326 17923583
Not checked in the free run.
- cites [38] Owen PJD, Sabit R, Lazarus JH. Thyroid disease and vascular function. Thyroid. 2007; 17(6): 519- 524. doi: 10.1089/thy.2007.0051 17614771
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCurrent clinical guidelines propose that thyroid hormone replacement therapy should not be routinely offered for adults with subclinical hypothyroidism.
“which is supported by current clinical guidelines proposing that thyroid hormone replacement therapy should not be routinely offered for adults with subclinical hypothyroidism.12,13,14”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [12] Bekkering GE, Agoritsas T, Lytvyn L,. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019; 365: l2006. doi: 10.1136/bmj.l2006 31088853 source
Not checked in the free run.
- cites [13] Pearce SHS, Brabant G, Duntas LH,. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013; 2(4): 215- 228. doi: 10.1159/000356507 24783053 PMC3923601 source
Not checked in the free run.
- cites [14] Jonklaas J, Bianco AC, Bauer AJ,; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014; 24(12): 1670- 1751. doi: 10.1089/thy.2014.0028 25266247 PMC4267409 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationResults from previous studies that examined associations of serum thyroid function within the normal range and various long-term adverse outcomes have been inconsistent across different populations.
“Results from previous studies5,33,34,35,36 that examined associations of serum thyroid function within the normal range and various long-term adverse outcomes have been inconsistent across different populations.”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [5] Inoue K, Tsujimoto T, Saito J, Sugiyama T. Association between serum thyrotropin levels and mortality among euthyroid adults in the United States. Thyroid. 2016; 26(10): 1457- 1465. doi: 10.1089/thy.2016.0156 27539006 source
Not checked in the free run.
- cites [33] Åsvold BO, Vatten LJ, Bjøro T,; Thyroid Studies Collaboration. Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts. JAMA Intern Med. 2015; 175(6): 1037- 1047. doi: 10.1001/jamainternmed.2015.0930 25893284 PMC4732559
Not checked in the free run.
- cites [34] Cappola AR, Arnold AM, Wulczyn K, Carlson M, Robbins J, Psaty BM. Thyroid function in the euthyroid range and adverse outcomes in older adults. J Clin Endocrinol Metab. 2015; 100(3): 1088- 1096. doi: 10.1210/jc.2014-3586 25514105 PMC4333030
Not checked in the free run.
- cites [35] Chaker L, van den Berg ME, Niemeijer MN,. Thyroid function and sudden cardiac death: a prospective population-based cohort study. Circulation. 2016; 134(10): 713- 722. doi: 10.1161/CIRCULATIONAHA.115.020789 27601558
Not checked in the free run.
- cites [36] Bano A, Dhana K, Chaker L,. Association of thyroid function with life expectancy with and without cardiovascular disease: the Rotterdam Study. JAMA Intern Med. 2017; 177(11): 1650- 1657. doi: 10.1001/jamainternmed.2017.4836 28975207 PMC5710266
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationSome recent studies have suggested that high-normal TSH concentrations are associated with increased risk of cardiovascular disease and mortality among the US general population or adults with chronic kidney disease.
“Meanwhile, some recent studies5,15,16 have suggested that even high-normal TSH concentrations are associated with increased risk of CVD and mortality among the US general population or adults with chronic kidney disease”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [5] Inoue K, Tsujimoto T, Saito J, Sugiyama T. Association between serum thyrotropin levels and mortality among euthyroid adults in the United States. Thyroid. 2016; 26(10): 1457- 1465. doi: 10.1089/thy.2016.0156 27539006 source
Not checked in the free run.
- cites [15] Rhee CM, Ravel VA, Streja E,. Thyroid functional disease and mortality in a national peritoneal dialysis cohort. J Clin Endocrinol Metab. 2016; 101(11): 4054- 4061. doi: 10.1210/jc.2016-1691 27525529 PMC5095247
Not checked in the free run.
- cites [16] Rhee CM, Kim S, Gillen DL,. Association of thyroid functional disease with mortality in a national cohort of incident hemodialysis patients. J Clin Endocrinol Metab. 2015; 100(4): 1386- 1395. doi: 10.1210/jc.2014-4311 25632971 PMC4399303
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationUnderlying cardiovascular status can be a modifier of the association between hypothyroidism and long-term adverse health outcomes.
“We included cross-product terms of exposure and mediator in the model given the previous findings that underlying cardiovascular status can be a modifier of the association between hypothyroidism and the long-term adverse health outcomes.28,29”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [28] Ro K, Yuen AD, Du L,. Impact of hypothyroidism and heart failure on hospitalization risk. Thyroid. 2018; 28(9): 1094- 1100. doi: 10.1089/thy.2017.0362 29897016 PMC6154446 source
Not checked in the free run.
- cites [29] Rhee CM, Curhan GC, Alexander EK, Bhan I, Brunelli SM. Subclinical hypothyroidism and survival: the effects of heart failure and race. J Clin Endocrinol Metab. 2013; 98(6): 2326- 2336. doi: 10.1210/jc.2013-1039 23720788 PMC3667266 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationown dataOur findings provide additional support for the importance of considering variations in the normative range of thyroid hormone levels when assessing long-term mortality risks in the general US population.
“Our findings provide additional support for the importance of considering variations in the normative range of thyroid hormone levels (statistically defined as between percentiles 2.5 and 97.5 in a healthy population) when assessing long-term mortality risks in the general US population.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataHigher TSH level may be a risk factor for CVD and also mortality, even when TSH levels are only modestly elevated.
“Our findings of increased risk of all-cause mortality among participants with subclinical hypothyroidism (defined by TSH >5.6 mIU/L) mediated by CVD, compared with those with middle-normal TSH concentrations, suggest that higher TSH level may be a risk factor for CVD and also mortality, even when TSH levels are only modestly elevated.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCollet et al reported that the mortality risk at lower TSH concentrations was slightly greater in men than in women.
“Moreover, Collet et al10 reported that the mortality risk at lower TSH concentrations was slightly greater in men than in women.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Collet T-H, Gussekloo J, Bauer DC,; Thyroid Studies Collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. 2012; 172(10): 799- 809. doi: 10.1001/archinternmed.2012.402 22529182 PMC3872478 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationWomen are at an increased risk of progression from subclinical to overt hypothyroidism.
“In general, it is well established that women are at an increased risk of progression from subclinical to overt hypothyroidism.4”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012; 379(9821): 1142- 1154. doi: 10.1016/S0140-6736(11)60276-6 22273398 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningOur findings indicate the importance of further investigations regarding clinical effectiveness of medical interventions (such as a CVD prevention program) for specific populations with subclinical hypothyroidism or even low-normal thyroid function.
“Although thyroid hormone therapy should not be routinely offered to patients with subclinical hypothyroidism, our findings indicate the importance of further investigations regarding clinical effectiveness of medical interventions (such as a CVD prevention program) for specific populations with subclinical hypothyroidism or even low-normal thyroid function.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious studies have found an increased risk of CVD and mortality among people with high-normal thyroid function partially mediated by anticoagulant factors.
“Previous studies10,34,36,43 have found an increased risk of CVD and mortality among people with high-normal thyroid function partially mediated by anticoagulant factors.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [10] Collet T-H, Gussekloo J, Bauer DC,; Thyroid Studies Collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. 2012; 172(10): 799- 809. doi: 10.1001/archinternmed.2012.402 22529182 PMC3872478 source
Not checked in the free run.
- cites [34] Cappola AR, Arnold AM, Wulczyn K, Carlson M, Robbins J, Psaty BM. Thyroid function in the euthyroid range and adverse outcomes in older adults. J Clin Endocrinol Metab. 2015; 100(3): 1088- 1096. doi: 10.1210/jc.2014-3586 25514105 PMC4333030
Not checked in the free run.
- cites [36] Bano A, Dhana K, Chaker L,. Association of thyroid function with life expectancy with and without cardiovascular disease: the Rotterdam Study. JAMA Intern Med. 2017; 177(11): 1650- 1657. doi: 10.1001/jamainternmed.2017.4836 28975207 PMC5710266
Not checked in the free run.
- cites [43] Bano A, Chaker L, de Maat MPM,. Thyroid function and cardiovascular disease: the mediating role of coagulation factors. J Clin Endocrinol Metab. 2019; 104(8): 3203- 3212. doi: 10.1210/jc.2019-00072 30938758
Not checked in the free run.
May combine two claims.
PremisecitationLow thyroid hormone levels increase systemic vascular resistance and induce endothelial dysfunction by reducing nitric oxide availability.
“Low thyroid hormone levels also increase systemic vascular resistance and induce endothelial dysfunction by reducing nitric oxide availability.37,38,39”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [37] Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007; 116(15): 1725- 1735. doi: 10.1161/CIRCULATIONAHA.106.678326 17923583 source
Not checked in the free run.
- cites [38] Owen PJD, Sabit R, Lazarus JH. Thyroid disease and vascular function. Thyroid. 2007; 17(6): 519- 524. doi: 10.1089/thy.2007.0051 17614771 source
Not checked in the free run.
- cites [39] Galli E, Pingitore A, Iervasi G. The role of thyroid hormone in the pathophysiology of heart failure: clinical evidence. Heart Fail Rev. 2010; 15(2): 155- 169. doi: 10.1007/s10741-008-9126-6 19110971 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA previous study from Norway found an association between high-normal TSH concentrations and CVD in women but not in men, consistent with our results.
“A previous study from Norway42 also found an association between high-normal TSH concentrations and CVD in women but not in men, consistent with our results.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Asvold BO, Bjøro T, Platou C, Vatten LJ. Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT study in Norway. Clin Endocrinol (Oxf). 2012; 77(6): 911- 917. doi: 10.1111/j.1365-2265.2012.04477.x 22724581
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious studies reported that low thyroid function even within the normal range is associated with metabolic syndrome owing to an increase in insulin resistance.
“Previous studies,5,6,7,40 including those using NHANES data,5,7 reported that low thyroid function even within the normal range is associated with metabolic syndrome owing to an increase in insulin resistance and might contribute to the progression of atherosclerosis and CVD risk.41”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [5] Inoue K, Tsujimoto T, Saito J, Sugiyama T. Association between serum thyrotropin levels and mortality among euthyroid adults in the United States. Thyroid. 2016; 26(10): 1457- 1465. doi: 10.1089/thy.2016.0156 27539006 source
Not checked in the free run.
- cites [6] Garduño-Garcia J de J, Alvirde-Garcia U, López-Carrasco G,. TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects. Eur J Endocrinol. 2010; 163(2): 273- 278. doi: 10.1530/EJE-10-0312 20516204 source
Not checked in the free run.
- cites [7] Le TN, Celi FS, Wickham EP III. Thyrotropin levels are associated with cardiometabolic risk factors in euthyroid adolescents. Thyroid. 2016; 26(10): 1441- 1449. doi: 10.1089/thy.2016.0055 27599541 PMC5067795 source
Not checked in the free run.
- cites [40] Roos A, Bakker SJL, Links TP, Gans ROB, Wolffenbuttel BHR. Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. J Clin Endocrinol Metab. 2007; 92(2): 491- 496. doi: 10.1210/jc.2006-1718 17090642 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe present study does not provide any information regarding the importance of treatment with thyroid hormone replacement if high TSH levels subsequently triggered medication use in NHANES participants.
“Thus, the present study does not provide any information regarding the importance of treatment with thyroid hormone replacement if high TSH levels subsequently triggered medication use in NHANES participants.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationElevated thyroid hormone levels negatively affect quality of life and cognitive function as well as the cardiovascular system in young and middle-aged populations.
“Elevated thyroid hormone levels have been reported to negatively affect quality of life and cognitive function as well as the cardiovascular system in young and middle-aged populations.4”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012; 379(9821): 1142- 1154. doi: 10.1016/S0140-6736(11)60276-6 22273398 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataA major strength of the study is estimation of a potential pathway from serum TSH concentrations to mortality through CVD in a large, nationally representative sample of the US general population with individualized linkage to the national mortality database with rigorous capture of death events.
“A major strength of our study includes estimation of a potential pathway from serum TSH concentrations to mortality through CVD in a large, nationally representative sample of the US general population with individualized linkage to the national mortality database with rigorous capture of death events.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe bias from nondifferential misclassification is not always toward the null in mediation analysis.
“Even though these are all likely causing nondifferential misclassifications, the bias this may generate is not always toward the null in mediation analysis.45”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] VanderWeele TJ. Mediation analysis: a practitioner’s guide. Annu Rev Public Health. 2016; 37: 17- 32. doi: 10.1146/annurev-publhealth-032315-021402 26653405
Not checked in the free run.
May combine two claims.
Study design and conductreasoningThe exposure-mediator association is not well defined temporally, and reverse causation is possible.
“Second, while it is unlikely that CVD affected serum TSH concentrations, the exposure-mediator association is not well defined temporarily, and we need to consider the possibility of reverse causation (ie, that the participants’ thyroid status prior to CVD was different from their thyroid status at the time of study entry).”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe data did not capture all CVD events during follow-up; therefore, the effect size of CVD mediation might be underestimated.
“In addition, our data did not capture all of the CVD events during the follow-up period; therefore, effect size of the CVD mediation might be underestimated.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).
PremisecitationTreatment with levothyroxine is recommended when serum TSH concentrations reach 10 mIU/L or greater.
“A previous meta-analysis8 reported that subclinical hypothyroidism is associated with higher CVD risk, and thus treatment with levothyroxine is recommended when serum TSH concentrations reach 10 mIU/L or greater.4,31”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [4] Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012; 379(9821): 1142- 1154. doi: 10.1016/S0140-6736(11)60276-6 22273398 source
Not checked in the free run.
- cites [31] Peeters RP. Subclinical hypothyroidism. N Engl J Med. 2017; 376(26): 2556- 2565. doi: 10.1056/NEJMcp1611144 28657873
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationIt remains unclear whether thyroid hormone replacement therapy is effective in mitigating several long-term adverse outcomes, such as CVD and death, in the general population with subclinical hypothyroidism.
“However, it remains unclear whether thyroid hormone replacement therapy is effective in mitigating several long-term adverse outcomes, such as CVD and death, in the general population with subclinical hypothyroidism.12”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Bekkering GE, Agoritsas T, Lytvyn L,. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019; 365: l2006. doi: 10.1136/bmj.l2006 31088853 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationCurrent clinical guidelines from the American Thyroid Association and European Thyroid Association do not recommend treating subclinical hypothyroidism when TSH is 10 mIU/L or less (and without symptoms in younger individuals).
“Current clinical guidelines from the American Thyroid Association14 and European Thyroid Association13 do not recommend treating subclinical hypothyroidism when TSH is 10 mIU/L or less (and without symptoms in younger individuals).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [14] Jonklaas J, Bianco AC, Bauer AJ,; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014; 24(12): 1670- 1751. doi: 10.1089/thy.2014.0028 25266247 PMC4267409 source
Not checked in the free run.
- cites [13] Pearce SHS, Brabant G, Duntas LH,. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013; 2(4): 215- 228. doi: 10.1159/000356507 24783053 PMC3923601 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThis recommendation has been followed by 2 recent comprehensive reviews that summarized the evidence arguing against clinical benefits of thyroid hormone replacement therapy toward quality of life or hypothyroid symptoms among adults, especially elderly individuals, with subclinical hypothyroidism.
“This recommendation has been followed by 2 recent comprehensive reviews1,12 that summarized the evidence arguing against clinical benefits of thyroid hormone replacement therapy toward quality of life or hypothyroid symptoms among adults, especially elderly individuals, with subclinical hypothyroidism.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1] Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: a review. JAMA. 2019; 322(2): 153- 160. doi: 10.1001/jama.2019.9052 31287527 source
Not checked in the free run.
- cites [12] Bekkering GE, Agoritsas T, Lytvyn L,. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019; 365: l2006. doi: 10.1136/bmj.l2006 31088853 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA previous meta-analysis reported that subclinical hypothyroidism is associated with higher CVD risk.
“A previous meta-analysis8 reported that subclinical hypothyroidism is associated with higher CVD risk, and thus treatment with levothyroxine is recommended when serum TSH concentrations reach 10 mIU/L or greater.4,31”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Rodondi N, den Elzen WPJ, Bauer DC,; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010; 304(12): 1365- 1374. doi: 10.1001/jama.2010.1361 20858880 PMC3923470 source
Not checked in the free run.
The paper relies on this without support.
Self-reported coronary artery disease and nonfatal cardiovascular disease events accurately classify prevalent cardiovascular disease.
“Coronary artery diseases and nonfatal CVD events (congestive heart failure, angina, myocardial infarction, or stroke) were ascertained by self-report at baseline.”
The paper relies on this without support.
Mortality data from death certificates provided by the National Death Index accurately ascertain all-cause mortality.
“Mortality data were ascertained by the National Center for Health Statistics from death certificate information provided by the National Death Index after record matching by Social Security number, name, date of birth, race/ethnicity, sex, state of birth, and state of residence.”
The paper relies on this without support.
The mediation analysis assumes no unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships.
“We used a marginal structural approach within the counterfactual framework.18,26,27”
The paper relies on this without support.
A single baseline serum TSH measurement adequately represents long-term thyroid function.
“Time to event was calculated from the day of TSH measurement to the end of follow-up or the death date.”
The authors state this as an assumption.
There are no other unmeasured confounders and no confounding between the mediator and outcome as affected by exposure.
“our mediation analysis was based on the assumption that there were no other unmeasured confounders and no confounding between the mediator and outcome as affected by exposure.45”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Cardiovascular disease mediates 14.3% of the association between subclinical hypothyroidism and all-cause mortality and 5.9% of the association between high-normal TSH and all-cause mortality.
“with CVD mediating 14.3 and 5.9% of the association, respectively (104).”
From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [104]
In 9,020 adults, subclinical hypothyroidism (TSH >5.60 mIU/L) is associated with increased all-cause mortality (HR = 1.90) compared with middle-normal TSH (1.20-1.95 mIU/L).
“SCH (TSH >5.60 mIU/L) and high-normal TSH (1.96–5.60 mIU/L) were associated with increased all-cause mortality (HR = 1.90 and 1.36) vs. the middle-normal TSH group (1.20–1.95 mIU/L) (104)”
From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [104]
High-normal TSH (1.96-5.60 mIU/L) is associated with increased all-cause mortality (HR = 1.36) compared with middle-normal TSH (1.20-1.95 mIU/L).
“High-normal TSH levels impact unfavorably on mortality.”
From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [104]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Subclinical hypothyroidism CVD missing-data percentage is incorrect
MinorTable 1 reports 3 participants with missing or unknown cardiovascular disease status as 0.2% of the 165-person subclinical hypothyroidism group. Three of 165 is approximately 1.8%.
Reported 0.2 · recomputed 1.818182
“Missing or unknown | 20 (0.7) | 10 (0.3) | 20 (0.7) | 3 (0.2)”
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Thyroid Function in the Euthyroid Range and Adverse Outcomes in Older Adults
Cappola, A. R., Arnold, A. M., Wulczyn, K., Carlson, M., Robbins, J., & Psaty, B. M. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3586 · Cited by 201 · see citing works
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The role of thyroid hormone in the pathophysiology of heart failure: clinical evidence
Galli, E., Pingitore, A., & Iervasi, G. (2010) · Heart Failure Reviews · doi:10.1007/s10741-008-9126-6 · Cited by 132 · see citing works
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Thyroid Disease and Vascular Function
Owen, P. J. D., Sabit, R., & Lazarus, J. H. (2007) · Thyroid · doi:10.1089/thy.2007.0051 · Cited by 101 · see citing works
Thyroid Function and Sudden Cardiac Death: A Prospective Population-Based Cohort Study
Chaker, L., van den Berg, M. E., Niemeijer, M. N., Franco, O. H., Dehghan, A., Hofman, A., Rijnbeek, P. R., Deckers, J. W., Eijgelsheim, M., Stricker, B. H. C., et al. (2016) · Circulation · doi:10.1161/circulationaha.115.020789 · Cited by 97 · see citing works
Subclinical hypothyroidism and survival: the effects of heart failure and race
Rhee, C. M., Curhan, G. C., Alexander, E. K., Bhan, I., & Brunelli, S. M. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1039 · Cited by 83 · see citing works
Self-citationEducation and Cause-specific Mortality
Nordahl, H., Lange, T., Osler, M., Diderichsen, F., Andersen, I., Prescott, E., Tjønneland, A. M., Frederiksen, B., & Rod, N. H. (2014) · Epidemiology · doi:10.1097/ede.0000000000000080 · Cited by 80 · see citing works
Thyroid Function Within the Normal Range and Risk of Coronary Heart Disease
Åsvold, B. O., VATTEN, L. J., Bjøro, T., Bauer, D. C., Bremner, A., Cappola, A. R., Ceresini, G., den Elzen, W. P. J., Ferrucci, L., Franco, O. H., et al. (2015) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2015.0930 · Cited by 77 · see citing works
Mediation analysis of the relationship between institutional research activity and patient survival
Rochon, J., du Bois, A., & Lange, T. (2014) · BMC Medical Research Methodology · doi:10.1186/1471-2288-14-9 · Cited by 76 · see citing works
Rhee, C. M., Kim, S., Gillen, D. L., Oztan, T., Wang, J., Mehrotra, R., Kuttykrishnan, S., Nguyen, D. V., Brunelli, S. M., Kovesdy, C. P., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-4311 · Cited by 67 · see citing works
Self-citationBano, A., Dhana, K., Chaker, L., Kavousi, M., Ikram, M. A., Mattace-Raso, F. U. S., Peeters, R. P., & Franco, O. H. (2017) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2017.4836 · Cited by 64 · see citing works
Inoue, K., Tsujimoto, T., Saito, J., & Sugiyama, T. (2016) · Thyroid · doi:10.1089/thy.2016.0156 · Cited by 63 · see citing works
Self-citationLow-Normal Thyroid Function and Novel Cardiometabolic Biomarkers
van Tienhoven‐Wind, L. J. N., & Dullaart, R. P. F. (2015) · Nutrients · doi:10.3390/nu7021352 · Cited by 53 · see citing works
Thyrotropin Levels Are Associated with Cardiometabolic Risk Factors in Euthyroid Adolescents
Le, T. N., Celi, F. S., & Wickham, E. P. (2016) · Thyroid® · doi:10.1089/thy.2016.0055 · Cited by 53 · see citing works
Urinary Iodine Concentration and Mortality Among U.S. Adults
Inoue, K., Leung, A. M., Sugiyama, T., Tsujimoto, T., Makita, N., Nangaku, M., & Ritz, B. R. (2018) · Thyroid · doi:10.1089/thy.2018.0034 · Cited by 40 · see citing works
Self-citationThyroid functional disease and mortality in a national peritoneal dialysis cohort.
Rhee, C. M., Ravel, V. A., Streja, E., Mehrotra, R., Kim, S., Wang, J., Nguyen, D. V., Kovesdy, C. P., Brent, G. A., & Kalantar-Zadeh, K. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-1691 · Cited by 36 · see citing works
Self-citationThyroid function and cardiovascular disease: the mediating role of coagulation factors.
Bano, A., Chaker, L., de Maat, M. P. M., Atiq, F., Kavousi, M., Franco, O. H., Mattace-Raso, F. U. S., Leebeek, F. W. G., & Peeters, R. P. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2019-00072 · Cited by 25 · see citing works
Impact of Hypothyroidism and Heart Failure on Hospitalization Risk
Ro, K., Yuen, A. D., Du, L., Ro, C. C., Seger, C., Yeh, M. W., Leung, A. M., & Rhee, C. M. (2018) · Thyroid · doi:10.1089/thy.2017.0362 · Cited by 23 · see citing works
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Thyroid disorders and cardiovascular manifestations: an update
Paschou, S. Α., Bletsa, E., Stampouloglou, P. K., Tsigkou, V., Valatsou, A., Stefanaki, K., Kazakou, P., Spartalis, Μ., Spartalis, E. D., Oikonomou, E. K., et al. (2022) · Endocrine · doi:10.1007/s12020-022-02982-4 · Cited by 132 · see citing works
“graphy, and especially male patients have higher total plaque burden when compared to females [90].”
BackgroundRatziu, V., Scanlan, T. S., & Bruinstroop, E. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.10.018 · Cited by 117 · see citing works
Levothyroxine for the Treatment of Subclinical Hypothyroidism and Cardiovascular Disease
Sue, L. Y., & Leung, A. M. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.591588 · Cited by 76 · see citing works
“11:591588. doi: 10.3389/fendo.2020.591588 MINI REVIEW published: 21 October 2020 doi: 10.3389/fendo.2020.591588 Levothyroxine for the Treatment of Subclinical Hypothyroidism and Cardiovascular Disease Laura Y. Sue1 and Angela M. Leung1,2* 1 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, U…”
InfluentialSelf-citationInoue, K., Streja, E., Tsujimoto, T., & Kobayashi, H. H. (2020) · Annals of Epidemiology · doi:10.1016/j.annepidem.2020.12.004 · Cited by 62 · see citing works
“, measurement of UACR) to the death record as the previous study did [21,22].”
Self-citationXu, Y., Derakhshan, A., Hysaj, O., Wildisen, L., Ittermann, T., Pingitore, A., Abolhassani, N., Medici, M., Kiemeney, L. A. L. M., Riksen, N. P., et al. (2023) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(23)00227-9 · Cited by 61 · see citing works
Self-citationWang, Y., Tan, H., Zheng, H., Ma, Z., Zhan, Y., Hu, K., Yang, Z., Yao, Y., & Zhang, Y. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.161895 · Cited by 53 · see citing works
Wu, Z., Yue, J., Li, P., Wang, Y., Zhang, H., Li, Z., Li, X., Tao, L., Gao, B., & Guo, X. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04276-3 · Cited by 51 · see citing works
“This method has been widely used in previous studies to quantify the mediating effect [42, 43].”
MethodLow awareness and under-diagnosis of hypothyroidism
Gottwald‐Hostalek, U., & Schulte, B. (2021) · Current Medical Research and Opinion · doi:10.1080/03007995.2021.1997258 · Cited by 43 · see citing works
Hypothyroidism and metabolic cardiovascular disease
Patrizio, A., Ferrari, S. M., Elia, G., Ragusa, F., Balestri, E., Botrini, C., Rugani, L., Mazzi, V., Antonelli, A., Fallahi, P., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1408684 · Cited by 52 · see citing works
“These results have also been con fi rmed in different populations all around the world such as USA (21) and Asia (22, 23).”
BackgroundUpdate on subclinical thyroid dysfunction
Hashimoto, K. (2022) · Endocrine Journal · doi:10.1507/endocrj.ej22-0182 · Cited by 44 · see citing works
“Other cross-sectional and longitudinal studies reported that SCH may be an independent risk factor for CHD and may increase the risk of cardiovascular outcomes [26-34].”
BackgroundMüller, P., Leow, M. K., & Dietrich, J. W. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.942971 · Cited by 39 · see citing works
“Similar observations were made in another populationbased study that found low-normal, high-normal and elevated TSH to be associated with higher all-cause mortality than middle-normal TSH (135).”
ResultChen, Y., Tian, S., Wu, J., Li, H., Li, S., Xu, Z., Liang, X., Adhikari, V. P., Xiao, J., Song, J.-Y., et al. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad016 · Cited by 33 · see citing works
Zhang, X., Wang, Y., Wang, H., & Zhang, X. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad558 · Cited by 29 · see citing works
Inoue, K., Nianogo, R. A., Telesca, D., Goto, A., Khachadourian, V., Tsugawa, Y., Sugiyama, T., Mayeda, E. R., & Ritz, B. R. (2020) · International Journal of Epidemiology · doi:10.1093/ije/dyaa263 · Cited by 29 · see citing works
“Cardiovascular disease was classified using ICD–10 codes I00–09, I11, I13, I20–51 and I60–69.27 Covariates Demographic variables included age, sex (male, female), race/ethnicity (non-Hispanic White, non-Hispanic Black, Mexican-American or others), citizenship status (US or other), educational status (less than high sc…”
MethodInfluentialSelf-citationWu, Z., Yue, J., Zhou, D., Chen, S., Zhao, Y., Zhang, H., Liu, Y., Li, X., Wang, W., Zhang, J., et al. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac110 · Cited by 24 · see citing works
Effect of coffee consumption on thyroid function: NHANES 2007-2012 and Mendelian randomization
Zhao, G., Wang, Z., Ji, J., & Cui, R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1188547 · Cited by 24 · see citing works
“Additionally, subclinical hypothyroidism is associated with a variety of cardiovascular diseases and all-cause mortality (37, 38).”
BackgroundSubclinical Thyroid Dysfunction and the Risk of Cardiovascular Disease
Stojković, M., & Žarković, M. (2020) · Current Pharmaceutical Design · doi:10.2174/1381612826666201118094747 · Cited by 23 · see citing works
Wan, H., Yu, G., He, Y., Liu, S., Chen, X., Jiang, Y., Duan, H., Xu, L., Liu, L., & Shen, J. (2024) · Annals of Medicine · doi:10.1080/07853890.2024.2318418 · Cited by 23 · see citing works
“…tsh was measured by microparticle enzyme immunoassay, serum Ft4 by two-step enzyme immunoassay and serum Ft3 by competitive binding immunoassay [25,26]. in the sPeeD-shunde study, blood samples were collected between 7:00 am and 10:00 am from participants who had fasted for 10 h. the levels of…”
MethodInfluentialAlomair, B. M., Al-Kuraishy, H. M., Al-Gareeb, A. I., Alshammari, M. A., Alexiou, A. T., Papadakis, M., Saad, . M., & Batiha, G. E. (2024) · Thyroid Research · doi:10.1186/s13044-024-00199-3 · Cited by 23 · see citing works
Wang, X., Wang, H., Li, Q., Wang, P., Xing, Y., Zhang, F., Li, J., & Shan, Z. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac417 · Cited by 20 · see citing works
Inoue, K., Guo, R., Lee, M. L., Ebrahimi, R., Neverova, N. V., Currier, J. W., Bashir, M. T., & Leung, A. M. (2022) · Thyroid · doi:10.1089/thy.2022.0393 · Cited by 20 · see citing works
Self-citationHu, M., Wei, J., Hu, Y., et al. (2022) · Environmental Research · doi:10.1016/j.envres.2022.114860 · Cited by 20 · see citing works
Decision Making in Subclinical Thyroid Disease
Evron, J. M., & Papaleontiou, M. (2021) · Medical Clinics of North America · doi:10.1016/j.mcna.2021.05.014 · Cited by 23 · see citing works
Relationship Between Subclinical Hypothyroidism and the Risk of Cardiovascular Complications
Kaushik, A., & Agrawal, M. (2023) · Cureus · doi:10.7759/cureus.33708 · Cited by 21 · see citing works
“T4 is one of the most significant regulators for monitoring cardiac activity and cardiovascular hemodynamics [16].”
BackgroundEffect of physical exercise in people with hypothyroidism: systematic review and meta-analysis
Duñabeitia, I., González-Devesa, D., Varela, S., Diz, J. C., & Ayán, C. (2023) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365513.2023.2286651 · Cited by 19 · see citing works
“It should also be noted that an increase in the risk of cardiovascular disease and mortality has been observed in people with SCH [8].”
BackgroundDuan, Q., Huang, H. F., Zhang, S., et al. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1389714 · Cited by 18 · see citing works
“The potential nonlinear association was assessed using a restricted cubic spline (RCS) model with three knots placed at the 10th, 50th, and 90th percentiles of CDAI (32, 33).”
MethodThe Two Faces of Janus: Why Thyrotropin as a Cardiovascular Risk Factor May Be an Ambiguous Target
Dietrich, J. W., Hoermann, R., Midgley, J. E. M., Bergen, F., & Müller, P. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.542710 · Cited by 19 · see citing works
“Our analysis suggests a possible mechanism linking TSH to cardiovascular complications, which is a sensible alternative to the thyroid failure hypothesis by other authors (16).”
BackgroundResultMachine Learning Coronary Artery Disease Prediction Based on Imaging and Non-Imaging Data
Kigka, V. I., Georga, E. I., Tsakanikas, V., Kyriakidis, S., Tsompou, P. I., Siogkas, P. K., Michalis, L. K., Naka, K. Κ., Neglia, D., Rocchiccioli, S., et al. (2022) · Diagnostics · doi:10.3390/diagnostics12061466 · Cited by 16 · see citing works
“In the presented model, we observe that the most significant predictor for the prognosis of CAD is thyroid stimulating hormone, which confirms the effect of the thyroid hormones on the cardiovascular system [29,30].”
BackgroundLi, J., Ren, Y., Wang, L., Zou, X., Ding, X., Hou, T., Zhang, Q., Tang, S., Han, X., Song, L., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14491 · Cited by 16 · see citing works
Wang, S., Gu, L., Chen, J. C., Jiang, Q., Sun, J., Wang, H., & Wang, L. (2022) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2022.109990 · Cited by 15 · see citing works
Thyrotropin inhibits osteogenic differentiation of human periodontal ligament stem cells
Zeng, Y., Deng, J., Jiang, Q.-L., Wang, C., Zhang, L., Li, T., & Jiang, J. (2023) · Journal of Periodontal Research · doi:10.1111/jre.13109 · Cited by 18 · see citing works
Luo, Y., Wu, F., Huang, Z., Gong, Y., & Zheng, Y. (2022) · Lipids in Health and Disease · doi:10.1186/s12944-022-01749-0 · Cited by 22 · see citing works
Holley, M., Razvi, S., Farooq, M. S., Dew, R., Maxwell, I., & Wilkes, S. (2024) · Systematic Reviews · doi:10.1186/s13643-024-02548-7 · Cited by 17 · see citing works
Iacoviello, M., Santamato, V., Pagano, A., & Marengo, A. (2025) · Frontiers in Digital Health · doi:10.3389/fdgth.2025.1583399 · Cited by 16 · see citing works
“Further investigations into the connection between subclinical hypothyroidism and cardiovascular diseases have also examined the potential for accurately predicting mortality and hospitalization in patients with HF (19, 20).”
Fang, H., Zhao, R., Cui, S., & Wan, W. (2022) · Aging · doi:10.18632/aging.204352 · Cited by 15 · see citing works
Campi, I., Dell’Acqua, M., Stellaria Grassi, E., Cristina Vigone, M., & Persani, L. (2023) · European Thyroid Journal · doi:10.1530/etj-23-0012 · Cited by 13 · see citing works
L-T4 therapy in the presence of pharmacological interferents
Benvenga, S. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.607446 · Cited by 13 · see citing works
“9% of the association, respectively (104).”
Iodine‐Induced Hypothyroidism and Long‐Term Risks of Incident Heart Failure
Inoue, K., Guo, R., Lee, M. L., Neverova, N. V., Ebrahimi, R., Currier, J. W., Bashir, M. T., & Leung, A. M. (2023) · Journal of the American Heart Association · doi:10.1161/jaha.123.030511 · Cited by 13 · see citing works
Self-citationA Clinical Debate: Subclinical Hypothyroidism
Jasim, S., Abdi, H., Gharib, H., & Biondi, B. (2021) · Intern J Endocrinol Metab · doi:10.5812/ijem.115948 · Cited by 15 · see citing works
“An association of SCH with ischemic heart disease and mortality was also suggested (28, 29).”
BackgroundLu, Y., Chen, S., Jin, H., et al. (2022) · Journal of Applied Toxicology · doi:10.1002/jat.4401 · Cited by 13 · see citing works
“X04), which referred to previous studies (Cai et al., 2020; Inoue et al., 2020).”
Wang, S., Sun, J., Gu, L., Wang, Y., Du, C., Wang, H., Ma, Y., & Wang, L. (2022) · Biological Trace Element Research · doi:10.1007/s12011-022-03451-9 · Cited by 12 · see citing works
Cardiovascular outcomes in subclinical thyroid disease: an update
Ettleson, M. D. (2023) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000818 · Cited by 15 · see citing works
Souza, D. S., Marques, L. P., Costa, A., Cruz, J. S., Rhana, P., Santos‐Miranda, A., Joviano‐Santos, J. V., Durço, A. O., de Vasconcelos, C. M. L., & Roman‐Campos, D. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120945 · Cited by 14 · see citing works
Wang, S., Gu, L., Zhu, J. W., Shan, T., Sun, J., Jiang, Q., Wang, H., Zhao, D., Wang, Q., & Wang, L. (2022) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2022.110116 · Cited by 13 · see citing works
Yu, G., Liu, S. M., Song, C., Ma, Q., Chen, X., Jiang, Y., Duan, H., He, Y., Wang, D., Wan, H., et al. (2024) · European Thyroid Journal · doi:10.1530/etj-23-0130 · Cited by 13 · see citing works
“In the NHANES datasets, serum TSH levels were measured using a microparticle enzyme immunoassay, serum FT4 levels were measured using a two-step enzyme immunoassay, and serum FT3 levels were measured using a competitive binding immunoenzymatic assay (27, 28).”
Isailă, O.-M., Stoian, V. E., Fulga, I., Piraianu, A. I., & Hostiuc, S. (2024) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd11040098 · Cited by 13 · see citing works
“A recently conducted joint study of 9020 U.S. adults, by Inoue et al., found that cardiovascular disease mediated the association between subclinical hypothyroidism and all-cause mortality, especially among women and the elderly [65].”
BackgroundUyar, G. C., & Kılıç, M. K. (2024) · BMC Geriatrics · doi:10.1186/s12877-024-05643-5 · Cited by 11 · see citing works
Association Between Carotid Atherosclerosis and Atrial Fibrillation, Cardiac, and Renal Function
Rimmele, D. L., Borof, K., Jensen, M., Behrendt, C., Cheng, B., Debus, E. S., Gerloff, C. P., & Thomalla, G. (2022) · European Journal of Vascular and Endovascular Surgery · doi:10.1016/j.ejvs.2022.01.010 · Cited by 11 · see citing works
Wang, S., Zhao, D., Yang, T., Deng, B., Sun, J., Gu, L., Wang, H., & Wang, L. (2023) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2023.01.007 · Cited by 10 · see citing works
Wang, L., Xu, H., Yang, Y., Guan, H., He, X., Wu, R., Wu, J., Yuan, N., Guo, T., Zhang, Y., et al. (2023) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2023.133094 · Cited by 10 · see citing works
Chen, J., Zhang, L., & Zhang, X. (2024) · Frontiers in Public Health · doi:10.3389/fpubh.2024.1366485 · Cited by 13 · see citing works
Zhang, Z., Wang, C., Lin, C., Wu, Y., Wei, J., Lu, J., Chen, B., Wu, C., Zhang, X., Yang, Y., et al. (2024) · The Lancet Regional Health - Western Pacific · doi:10.1016/j.lanwpc.2024.101222 · Cited by 11 · see citing works
“38,39 If the relationship was found to be nonlinear, a recursive algorithm was employed to determine the in fl ection point between O 3 exposure and CVD mortality.”
MethodT4 rather than TSH correlates with BMD among euthyroid adults
Sheng, N., Xing, F., Wang, J., Duan, X., & Xiang, Z. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1039079 · Cited by 10 · see citing works
Liu, G., Ren, M., Du, Y., Zhao, R., Wu, Y. F., Liu, Y., & Liang, Q. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1263861 · Cited by 10 · see citing works
“Inadequate serum thyroid hormone levels impair cardiac function and may result in multiple cardiovascular risk factors, such as endothelial dysfunction, increased intima-media thickness, increased vascular resistance, and pericardial effusion (3).”
BackgroundQin, Z., Muhanhali, D., & Ling, Y. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad735 · Cited by 12 · see citing works
Nilkantham, S., Singh, A., Majumdar, V., Harini, K. N., & Snigdha, A. (2025) · Journal of Medical Internet Research · doi:10.2196/54078 · Cited by 12 · see citing works
“Hence, the TSH screening test is considered essential for thyroid dysfunction, and a disproportionately high concentration of TSH may warrant thyroxine and triiodothyronine measurements as well [8-10].”
Lifestyle Interventions to Tackle Cardiovascular Risk in Thyroid Hormone Signaling Disorders
Rodolfi, S., Rurale, G., Marelli, F., Persani, L., & Campi, I. (2025) · Nutrients · doi:10.3390/nu17132053 · Cited by 14 · see citing works
“…between subclinical hypothyroidism, impaired endothelial function [27,28], dyslipidemia, increased insulin resistance, hypertension and left ventricular dysfunction have been reported [34,35], the significance of the impact of hypothyroidism on CVDs and CV mortality remains undefined [36].”
Dell'Aquila, M., Rossi, C. S., Caldonazo, T. M. M., Cancelli, G., Harik, L., Soletti, G. J., An, K. R., Leith, J., Kirov, H., Ibrahim, M., et al. (2024) · JTCVS Open · doi:10.1016/j.xjon.2024.02.009 · Cited by 10 · see citing works
Autoimmune Thyroid Disease in the United States: Population Prevalence, Diagnosis Rates, and Trends
Dillon, C. F., Weisman, M. H., Leung, A. M., Brent, G. A., & Miller, F. W. (2025) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaf120 · Cited by 9 · see citing works
Self-citationAbdul, M. R., Rahim, S. M., & Saleh, A. (2023) · HAYATI Journal of Biosciences · doi:10.4308/hjb.30.6.1054-1060 · Cited by 8 · see citing works
“Numerous research have investigated the potential links between subclinical hypothyroidism and CVD (Leong et al. 2017; Inoue et al. 2020).”
BackgroundGu, L., Wang, S., Du, C., Deng, B., Ma, Y., Yang, T., Shan, T., Sun, J., Wang, H., & Wang, L. (2023) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15078 · Cited by 8 · see citing works
“During the 200 018 person-years of follow-up (median follow-up, 16.8 years; the maximum follow-up, 20.8 years), 3528 deaths T A B L E 1 B as el in e ch ar ac te ri st ic s o f th e st ud y po pu la ti o n C en ti le s o f G G ap (% ) C ha ra ct er is ti c O ve ra ll 1 st -5 th 6 th -2 0 th 2 1 st -4 0 th 4 1 st -6 0 t…”
MethodInfluentialIs subclinical hypothyroidism associated with cardiovascular disease in the elderly?
Yamamoto, K., Nakano, Y., Soejima, Y., Suyama, A., Oguni, K., Hasegawa, K., & Otsuka, F. (2025) · Endocrine Connections · doi:10.1530/ec-24-0601 · Cited by 8 · see citing works
“A study using data from the National Health and Nutrition Examination Survey in the United States revealed that SCH was associated with all-cause mortality mediated by cardiovascular disease (CVD) (6).”
Kim, H., Jung, D. Y., Lee, S., Cho, J., Yim, H. W., & Kim, H. (2022) · Journal of Diabetes · doi:10.1111/1753-0407.13315 · Cited by 7 · see citing works
“Subclinical hypothyroidism, along with hypothyroidism, has been medically evaluated as a risk factor for cardiovascular diseases.(30) In this study, in the euthyroid state, the lower the TSH level, the higher the heart rate, and the tendency to increase significantly even after 2 years.”
BackgroundAl-Gburi, A. J. J., Al-Obaidi, S. R. Y., & Abdullah, W. H. (2023) · Ghana Medical Journal · doi:10.4314/gmj.v57i1.6 · Cited by 7 · see citing works
Brenta, G., Nepote, A., Barreto, A., Musso, C., Faingold, C., Fossati, P., Antonelli, A., Fallahi, P., Famà, F., & Meroño, T. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1162626 · Cited by 7 · see citing works
Yuan, J., Jin, Z., Qin, Y., et al. (2024) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2024.01.032 · Cited by 7 · see citing works
Nanoscale organization of cardiac calcium channels is dependent on thyroid hormone status
Charest, A., Nasta, N., Siddiqui, S., Menkes, S., Thomas, A., Saad, D., Forman, J., Huang, X., Sison, C. P., Gerdes, A. M., et al. (2024) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00272.2024 · Cited by 7 · see citing works
Associations of thyroid hormones with chronic diarrhea and constipation in euthyroid individuals
Zeng, W., Wang, Y., & Zhang, L. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1395743 · Cited by 7 · see citing works
“Participants were classi fi ed as euthyroid if their serum TSH and FT4 levels were within the normal limits (16, 17).”
BackgroundInfluentialGökkaya, N., & Aydın, K. (2024) · Scientific Reports · doi:10.1038/s41598-024-78185-w · Cited by 6 · see citing works
“Hypothyroidism, even subclinical hypothyroidism, has been associated with various health problems such as dyslipidemia, hypertension, obesity, and diabetes 19–21 .”
Ni, W.-C., Kong, S., Lin, K., Huang, Y., Li, J., Shi, S., Lu, Y.-C., Cheng, L., Chen, C., & Zhou, H. (2023) · European journal of medical research · doi:10.1186/s40001-023-01149-9 · Cited by 7 · see citing works
“Patients with high normal TSH were at greater risk of all-cause death and CVD than those with mid- to normal TSH [22].”
BackgroundZhang, F., Wan, Y., Tang, H., Zhao, D., Zhu, S., Ruan, L., & Zhu, W. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.167093 · Cited by 6 · see citing works
Yao, L., Ni, J., Wei, M., Li, T., Long, Z., Shi, J., & Tian, J. (2024) · European Neurology · doi:10.1159/000540277 · Cited by 8 · see citing works
“We used restricted cubic spline fi tted for logistic models with three knots at the 25th, 50th, and 75th percentiles of depression scores and a p value for nonlinearity was calculated [29].”
Fang, X., Hu, R., Fei, S., Ding, Z., Zhao, J., & Shang, J. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1437386 · Cited by 6 · see citing works
“Kosuke et al. discovered that CVDs acted as a mediator connecting SCH and high-normal TSH levels with all-cause mortality among US adults, especially in women and the elderly, suggesting possible threats to the health of patients even with only mildly elevated TSH levels (22).”
BackgroundLu, X., Wang, A., Liu, K., Chen, Y., Chen, W., Mao, Y., & Ye, D. (2024) · Biological Trace Element Research · doi:10.1007/s12011-024-04395-y · Cited by 6 · see citing works
“In this study, we used restricted cubic spline models with three knots, corresponding to the 10th, 50th, and 90th percentiles [33–35].”
Sun, Q., Wang, S., Han, X., Gu, L., Wang, H., Yang, Q., & Wang, L. (2025) · BMC Public Health · doi:10.1186/s12889-025-22428-6 · Cited by 6 · see citing works
“Furthermore, to explore the dose-response relationship between VAI and mortality, restricted cubic spline (RCS) regression with 3 default knots at the 10th, 50th and 90th percentiles of VAI was conducted for visualization [27].”
Che, W., Wang, Y., Wang, X., & Lyu, J. (2022) · Frontiers in Public Health · doi:10.3389/fpubh.2022.1000415 · Cited by 6 · see citing works
Song, J., Hu, J., Li, L., Xu, Z., Li, J., Sun, S., & Chen, C. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1323994 · Cited by 6 · see citing works
Liu, K., Lu, X., Wang, A., Chen, W., Chen, Y., Li, J., Sun, X., Huang, L., He, Z., Wen, C., et al. (2024) · Nutrition Journal · doi:10.1186/s12937-024-00992-8 · Cited by 6 · see citing works
“Given the complex survey designs adopted by NHANES, all estimates accounted for sample weights, clustering, and stratification [19].”
MethodFolate deficiency may increase the risk for elevated TSH in patients with type 2 diabetes mellitus
Lin, L., Du, Y., Niu, G., Xia, S., & Liu, J. (2023) · BMC Endocrine Disorders · doi:10.1186/s12902-023-01422-2 · Cited by 5 · see citing works
“Subclinical hypothyroidism and elevated TSH concentration is associated with an increased risk for CVD and all-cause mortality, particularly in individuals with high CVD risk (e.g. T2DM patients) [12, 13].”
BackgroundLipid Profile Pitfalls in Subclinical Hypothyroidism Pathophysiology and Treatment
Nicolaou, M., & Toumba, M. (2024) · Lipidology · doi:10.3390/lipidology1020008 · Cited by 5 · see citing works
Fan, M., Song, S., Chu, T., Li, R., Yue, M., Li, X., & Yang, J. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1458039 · Cited by 5 · see citing works
Chen, J., Lin, S., Wang, X., et al. (2023) · Biological Trace Element Research · doi:10.1007/s12011-023-03727-8 · Cited by 5 · see citing works
“For example, Mg is the raw material of various enzymes and coenzymes, and regulates energy metabolism, bone development, and neuromuscular excitability [3].”
Causal inference and machine learning in endocrine epidemiology
Inoue, K. (2024) · Endocrine Journal · doi:10.1507/endocrj.ej24-0193 · Cited by 5 · see citing works
“Another study investigated how subclinical hypothyroidism and high-normal serum thyrotropin (TSH) levels contribute to mortality mediated through cardiovascular disease [10].”
Self-citationLi, J., Wan, S., Dai, X., Cui, Y., & Lu, Z. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1530025 · Cited by 5 · see citing works
Prognostic Value of Normal Thyroid Stimulating Hormone in Long-Term Mortality in Patients With STEMI
Sun, L., Xiao, K., Miao, Z., Zhang, Y., Jin, S., Shi, N., Zhang, H., Zhao, T., & Li, J. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.806997 · Cited by 5 · see citing works
“(32) have reported that a U-curved association between TSH and the risk of all-cause mortality in the cohort study of 9,020 US adults and higher TSH levels (>1.”
Background2023 Korean Thyroid Association Management Guidelines for Patients with Subclinical Hypothyroidism
Chung, H. K., Ku, E. J., Yoo, W. S., Kang, Y. E., Kim, K. J., Kim, B. H., Kim, T. Y., Park, Y. J., Ahn, C. H., Yoon, J. H., et al. (2023) · International Journal of Thyroidology · doi:10.11106/ijt.2023.16.1.32 · Cited by 6 · see citing works
Inoue, K., Noh, J. Y., Yoshihara, A., Watanabe, N., Matsumoto, M., Fukushita, M., Suzuki, N., Hoshiyama, A., Mitsumatsu, T., Suzuki, A., et al. (2021) · Journal of the Endocrine Society · doi:10.1210/jendso/bvab181 · Cited by 5 · see citing works
“Ample evidence has shown that, if untreated or uncontrolled, such hypothyroid status increases the risk of long-term adverse health outcomes (eg, cardiovascular disease and death) [7-11].”
BackgroundSelf-citationTsilingiris, D., Stratigou, T., Kounatidis, D., Vallianou, N. G., Karampela, Ι., & Dalamaga, Μ. (2025) · Metabolism Open · doi:10.1016/j.metop.2025.100394 · Cited by 4 · see citing works
“Overall, the net result is an increased incidence of cardiovascular events in SH than the general population, which also mediates the association of SH with an increased overall mortality [40], particularly in those with TSH levels ≥ 10 mIU/L [4,41].”
Janovsky, C. C. P. S., Meneghini, V., Tebar, W. R., Martins, J. R. M., Sgarbi, J. A., Teixeira, P. D. F. D. S., Santos, I. S., Jones, S. R., Blaha, M. J., Toth, P. P., et al. (2025) · Metabolites · doi:10.3390/metabo15090606 · Cited by 4 · see citing works
“Such deficits exacerbate cardiovascular risk by fostering frailty, reducing metabolic resilience, and weakening immune responses [5,20].”
Heidarpour, M., Rezvanian, P., Sadri, M. A., Keshavarzrad, P., Zakeri, R., Vakilbashi, O., Shafie, D., Shekarchizadeh, M., Zarfeshani, S., Rabanipour, N., et al. (2023) · BioMed Research International · doi:10.1155/2023/4711275 · Cited by 4 · see citing works
Wang, Y., Yuan, Y., Mo, S., Wang, F., Wei, J., Yao, Y., Zeng, Y., & Zhang, Y. (2024) · Science China Life Sciences · doi:10.1007/s11427-024-2718-9 · Cited by 5 · see citing works
“To depict the C-R relationships between long-term exposure to PM 2.5 constituents and all-cause mortality, we adopted restricted cubic spline function with three knots at the 10th, 50th and 90th percentiles to smooth the exposure of interest in the multivariable-adjusted model (Inoue et al., 2020).”
InfluentialHypothyroidism predicts worsened prognosis in patients undergoing percutaneous coronary intervention
Cohen, B., Bental, T., Perl, L., Assa, H. V., Codner, P., Orvin, K., Talmor‐Barkan, Y., Levi, A., Kornowski, R., & Perl, L. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.984952 · Cited by 4 · see citing works
Rhee, C. M., You, A. S., Narasaki, Y., Brent, G. A., Sim, J. J., Kovesdy, C. P., Kalantar‐Zadeh, K., & Nguyen, D. V. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad261 · Cited by 3 · see citing works
Self-citationZhao, S., Zhang, B., Han, Y., Guan, J., Fang, W., Zhang, H., & Wang, A. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1185782 · Cited by 4 · see citing works
“org CVD in the general population (53, 54).”
BackgroundHoffmann, M. A., Knoll, S. N., Baqué, P.-E., Rosar, F., Scharrer, I., Reuss, S., & Schreckenberger, M. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12185905 · Cited by 4 · see citing works
“analyzed data based on a nationally representative database of US adults [20].”
BackgroundMethodLiu, X., Wong, C. K. H., Chan, W., Tang, E. H. M., Woo, Y. C., Liu, S. Y., Lam, C. L. K., & Lang, B. H. (2022) · BJS Open · doi:10.1093/bjsopen/zrac079 · Cited by 4 · see citing works
Best Achievements in Clinical Thyroidology in 2020
Lee, E. K., & Park, Y. J. (2021) · Endocrinology and Metabolism · doi:10.3803/enm.2021.103 · Cited by 4 · see citing works
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“To explore the concentration-response (C-R) relationship between PM 2.5 concentrations and prevalence of thyroid nodules, PM 2.5 was fitted as a smooth term in age-and sex-adjusted models using a restricted cubic spline (RCS) with three knots at the 10th, 50th, and 90th percentiles [43].”
InfluentialCentral hypothyroidism and cardiovascular disease: a Spanish cohort observational study
Guerrero‐Pérez, F., Iglesias, P., Fano, M. P., Rodríguez, M. D. M., Biagetti, B., Cordido, F., Novoa-Testa, I., García-Centeno, R., Fernández, L. G., Araujo-Castro, M., et al. (2025) · HORMONES · doi:10.1007/s42000-025-00707-6 · Cited by 4 · see citing works
Liu, L., Zhang, H., Chen, X., Liu, Z., Zhao, H.-Y., Ma, S., Zhao, M., Shen, P., Sun, Y., Lin, H., et al. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1640086 · Cited by 4 · see citing works
“Additionally, population-based studies have also illustrated that SCH increases the incidence of heart failure, coronary heart disease, and stroke and thereby increases the risk of cardiovascular mortality and all-cause mortality (9 – 12).”
- Authors
- Inoue, K., Ritz, B., Brent, G. A., Ebrahimi, R., Rhee, C. M., & Leung, A. M.
- Affiliations
- University of California, Los Angeles (US)
- University of California, Irvine (US)
- Corresponding author
- Inoue, Kosuke
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2020-02-07
- Volume
- 3
- Issue
- 2
- Pages
- e1920745
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC12064075
- OpenAlex
- W3005006611
- Semantic Scholar
- 3f19a13e8db57a3ff39575d0c47927ac5942739c
- Cited by
- 191
- References
- 41
- Citations by year
- 2026: 19 · 2025: 39 · 2024: 42 · 2023: 41 · 2022: 31 · 2021: 13 · 2020: 6
- FWCI
- 17.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P2CHD041022)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- subclinical hypothyroidism, cardiovascular disease, all-cause mortality, thyroid-stimulating hormone, mediation analysis, natural direct and indirect effects, free thyroxine, thyroid function
- MeSH terms
- Adult, Aged, Cardiovascular Diseases, Cause of Death, Female, Humans, Hypothyroidism, Male, Middle Aged, Nutrition Surveys, Risk Factors, Thyrotropin, United States, Cohort Studies, Proportional Hazards Models
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